Development Of Hyperprolactinemia Research Articles

Peony-Glycyrrhiza Decoction for Antipsychotic-Related Hyperprolactinemia in Patients with Schizophrenia: A Randomized Controlled Trial

Most antipsychotic drugs are dopamine receptor antagonists that usually lead to abnormal increases in prolactin concentrations and the development of hyperprolactinemia (HPRL), which in turn causes sexual dysfunction in patients. Peony-Glycyrrhiza Decoction (PGD) enhanced dopamine D2 receptors (DRD2) and dopamine transporter (DAT) and significantly reversed the expression of DRD2 and DAT. Therefore, we hypothesized that PGD might effectively improve hyperprolactinemia and alleviate sexual dysfunction in patients. We performed an 8-week randomized controlled study on 62 subjects with schizophrenia who were randomized into two groups. The experimental group was treated with the PGD intervention, and the control group did not receive treatment. The primary outcome indicators were the levels of sex hormones and the total Arizona Sexual Experience Scale (ASEX) score. There was a significant difference in PRL levels between the two groups at weeks 4 and 8. From the beginning to the end of the experiment, there was a significant increase in PRL levels in the control group, while there was no significant change in the experimental group. The ASEX scale assessed sexual function in both groups, and patients in the experimental group showed an improvement in sexual function at week 8. During the experiment, the two groups found no differences between Positive and Negative Syndrome Scale (PANSS) scores and Treatment Emergent Symptom Scale (TESS) scores. PGD significantly improved the patient's sexual function but was less effective in reducing prolactin levels and may prevent further increases in prolactin levels.

Association of the Level of Serum Prolactin with Polymorphic Variants of the GRIN2A, GPM3, and GPM7 Genes in Patients with Schizophrenia Taking Conventional and Atypical Antipsychotics

The dopamine, serotonin and glutamate systems are jointly involved in the pathogenesis and pharmacotherapy of schizophrenia. We formulated a hypothesis that polymorphic variants of the GRIN2A, GRM3, and GRM7 genes may be associated with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics as basic treatment. 432 Caucasian patients diagnosed with schizophrenia were examined. DNA was isolated from peripheral blood leukocytes using the standard phenol-chloroform method. For pilot genotyping, 12 SNPs in the GRIN2A gene, 4 SNPs in the GRM3 gene, and 6 SNPs in the GRM7 gene were selected. Allelic variants of the studied polymorphisms were determined by real-time PCR. The level of prolactin was determined by enzyme immunoassay. Among persons taking conventional antipsychotics, there were statistically significant differences in the distribution of genotype and allele frequencies in groups of patients with normal and elevated prolactin levels for the GRIN2A rs9989388 and GRIN2A rs7192557 polymorphic variants, as well as differences in serum prolactin levels depending on the genotype of the GRM7 rs3749380 polymorphic variant. Among persons taking atypical antipsychotics, statistically significant differences were found in the frequencies of genotypes and alleles of the GRM3 rs6465084 polymorphic variant. An association of polymorphic variants of the GRIN2A, GRM3, and GRM7 genes with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics has been established for the first time. The identified associations of polymorphic variants of the GRIN2A, GRM3 and GRM7 genes with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics have been established for the first time. These associations not only confirm the close connection of the dopaminergic, serotonergic, and glutamatergic systems in the development of schizophrenia, but also demonstrate the potential of taking into account the genetic component during therapy.

Anxiety level as a factor in the development of hyperprolactinemia in adolescent girls

One of the main factors in the regulation of the menstrual cycle is prolactin, the level of which begins to change actively with the onset of puberty. Anxiety is one of the main characteristics of a person’s psychological profile. Therefore, by acting on the level of anxiety, we can neutralize the effect of chronic and/or acute stress on the hypothalamic-pituitary system, including the level of prolactin.The objective: was to determine the correlations between different levels of anxiety and the presence of hyperprolactinemia, to study the possibilities of correcting the level of prolactin by means of complex anti-stress therapy.Materials and methods. To achieve this goal, we conducted a survey of 94 adolescent girls during the period of the formation of menstrual function. To study the psychoemotional state of the patients, the Spielberger-Hanin anxiety scale was used.Results. Among girls 14.0±1.5 years old with hyperprolactinemia, the presence of acute and chronic stress was revealed in 92.2% of cases. Before treatment, the proportion of high personal anxiety in girls with hyperprolactinemia was 4 times higher, and low personal anxiety was 6 times lower than in healthy women. The proportion of high situational anxiety significantly exceeded this indicator in healthy girls, moderate situational anxiety in girls with hyperprolactinemia was 3 times lower than in healthy women. And the proportion of low situational anxiety in girls with hyperprolactinemia was almost 5 times lower than in healthy women. Three months after the start of treatment, the proportion of high and moderate personal anxiety in girls with hyperprolactinemia decreased slightly, and the proportion of low personal anxiety increased significantly after the psychological correction. In contrast to personal anxiety, situational anxiety depends on living conditions, therefore, its changes were significant after anti-stress treatment. But even without psychological correction, positive changes were noted in girls with hyperprolactinemia. After treatment, the level of prolactin on average in girls with hyperprolactinemia decreased by 49.4% and reached normal values, while in girls without treatment, the level of prolactin decreased by only 20.5% and its level remained slightly above the upper limit of the norm.Conclusion. The fact that 92.2% of girls with hyperprolactinemia have acute or chronic stress and high situational anxiety (70.3%) and high personal anxiety (39.1%) indicates a direct correlation between high levels of anxiety and the presence of hyperprolactinemia, which confirms the need for conducting complex anti-stress therapy in girls with hyperprolactinemia.

New approaches to pharmacogenetics of drug-induced hyperprolactinemia in patients with schizophrenia

The pathogenesis of the development of drug-induced disorders while taking antipsychotic drugs is not well understood. The aim of the work is to study polymorphic variants of the multidrug resistance protein gene and genes encoding the metabolism and synthesis of dopamine and serotonin enzymes in antipsychotic-induced hyperprolactinemia in schizophrenia patients. As a result of a comprehensive study of 446 patients with schizophrenia and genotyping of 25 polymorphic variants of the MDR1, COMT, MAO-A, MAO-B, TPH1 and TPH2 genes, associations of polymorphisms rs1045642, rs2032582, rs4148739 (MDR1), rs6323 (MAO-А), rs1799836 (MAO-B) were revealed with the development of hyperprolactinemia. Further research is needed to develop personalized approaches to therapy.

Association between prolactin gene polymorphism (–1149 G/T) and hyperprolactinemia in anti-psychotic treated patients with schizophrenia

Hyperprolactinemia (HPRL) is a classical side effect of anti-psychotic drugs. Extrapituitary prolactin (PRL) production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism – 1149 G/T (rs134,1239) in prolactin gene. We examined whether this polymorphism is associated with hyperprolactinemia in patients with schizophrenia. The experimental group comprised 443 patients with schizophrenia. The control group comprised 126 healthy persons. The PRL concentration was measured in serum using the AccuBind ELISA Microwells kit. The functional polymorphism – 1149 G/T (rs134,1239) of the PRL gene was genotyped using the The MassARRAY® system. Genotype and allele frequencies were compared using χ2 test. A total of 227 patients suffered from HPRL (98 males/129 females) according to the criteria of hyperprolactinemia. The frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects. A comparison between patients with schizophrenia with and without hyperprolactinemia revealed that the frequency of G allele in patients with hyperprolactinemia is significantly higher than in patients without hyperprolactinemia (χ2 = 7.25; P = 0.007; OR = 1.44 [1.10–1.89]). Accordingly, the genotype GG was found to be more often in patients with hyperprolactinemia than without it (χ2 = 9.49; P = 0.009). A significant association of the polymorphic variant rs134,1239 with the development of hyperprolactinemia in patients with schizophrenia treated with anti-psychotic drugs was revealed. Therefore, the serum concentration of prolactin in anti-psychotic treatment patients with schizophrenia may also give an indication of the activity of gene regulating extrapituitary prolactin expression.The study was supported by the Russian Science Foundation, Grant 14-35-00023.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Prolactin gene polymorphism (− 1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics

BackgroundAntipsychotic drugs can cause hyperprolactinemia. However, hyperprolactinemia was also observed in treatment-naive patients with a first schizophrenic episode. This phenomenon might be related to the role of prolactin as a cytokine in autoimmune diseases. Extrapituitary prolactin production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism −1149 G/T (rs1341239). We examined whether this polymorphism was associated with hyperprolactinemia in patients with schizophrenia. MethodWe recruited 443 patients with schizophrenia and 126 healthy controls. The functional polymorphism −1149 G/T (rs1341239) in the prolactin gene was genotyped with multiplexed primer extension, combined with MALDI-TOF mass spectrometry. Genotype and allele frequencies were compared between groups with the χ2 test and logistic regression models adjusting for covariates. ResultsThe frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects. A comparison between patients with schizophrenia with and without hyperprolactinemia revealed significantly higher frequency of the G allele in patients with hyperprolactinemia than in patients without it (χ2=7.25; p=0.007; OR=1.44 [1.10–1.89]). Accordingly, patients with hyperprolactinemia carried the GG genotype more frequently than patients without hyperprolactinemia (χ2=9.49; p=0.009). This association remained significant after adjusting the estimates for such covariates as sex, age, duration of the diseases and the dose of chlorpromazine equivalents. ConclusionThis study revealed a significant association between the polymorphic variant rs1341239 and the development of hyperprolactinemia in patients with schizophrenia. The serum prolactin concentration in patients with schizophrenia treated with antipsychotics may provide an indication of the activity of the gene that regulates extrapituitary prolactin production which is believed to play a role in the immune system.

P.3.b.037 - Gene polymorphism of serotonin receptors and drug-induced hyperprolactinemia in schizophrenic patients

Background: Antipsychotics have been used for more than 50 years in the treatment of schizophrenia and many other psychiatric disorders. Schizophrenic patients have to take antipsychotic medication for a long time, often throughout the life [1]. Hyper prolactinemia in these patients is a common and serious side effect of therapy with atypical antipsychotics. Genes coding for serotonin receptors are considered as candidate genes responsible for the particular antipsychotic effects of neuroleptics [2]. The present study aimed to investigate the role of polymorphisms of the serotonin receptors genes (HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B, HTR6) in the pathogenesis of antipsychotic-induced hyperprolactinemia in patients with schizophrenia. Methods: 446 Russian patients with schizophrenia were examined, including 225 women and 221 men. The average age of patients was 42.1±1.4 years. Evaluation of serum prolactin performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 29 polymorphic variants of the serotonin receptor genes HTR1A (rs6295, rs1364043, rs10042486, rs1800042, rs749099), HTR1B (rs6298, rs6296, rs130058), HTR2A (rs6311, rs6313, rs6314, rs7997012, rs1928040, rs9316233, rs2224721, rs6312), HTR2C (rs6318, rs5946189, rs569959, rs17326429, rs4911871, rs3813929, rs1801412, rs12858300), HTR3A (rs1062613, rs33940208, rs1176713), HTR3B (rs1176744) and HTR6 (rs1805054). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between polymorphisms of relevant 5-HT receptor genes and antipsychotic drug-induced hyperprolactinemia in patients with schizophrenia from Siberia. All patients with schizophrenia were divided into two groups: those with and without hyperprolactinemia. Statistically significant results were obtained for polymorphic variants of the genes rs6312 HTR2A (χ2 = 4.685; p = 0.030), rs12858300 HTR2C, rs569959 HTR2C, which suggests the participation of these polymorphic variants in the development of hyperprolactinemia. When men and women were studied separately, only rs569959 HTR2C (χ2 = 6.284; p = 0.043) in men reached the nominal significance threshold. This finding is probably related to the X-bound character of HTR2C (i.e., men are hemizygotes). Also, we found a statistically significant association rs12858300 HTR2C (χ2 = 9.429; p = 0.002) in the female group. We did not find statistically significant association for other polymorphisms HTR1A (rs6295, rs1364043, rs10042486, rs1800042, rs749099), HTR1B (rs6298, rs6296, rs130058), HTR2A (rs6311, rs6313, rs6314, rs7997012, rs1928040, rs9316233, rs2224721), HTR2C (rs6318, rs5946189, rs17326429, rs4911871, rs3813929, rs1801412), HTR3A (rs1062613, rs33940208, rs1176713), HTR3B (rs1176744) and HTR6 (rs1805054). Though hyperprolactinemia is primarily attributed to blockade of DRD2 in the pituitary gland, the secretion of prolactin is also modulated by 5-HT. The involvement of the HTR1A, HTR2A, HTR2C, and HTR3 in the serotonergic-induced prolactin response is well documented. Conclusion: Our results indicate that genetic variants of HTR2C may have functional consequences on the modulation of prolactin secretion. Further search for genetic markers associated with the development of side effects of neuroleptic therapy, will contribute to the development of effective methods of diagnosis, correction and treatment of disease, as well as of adherence of patients with mental disorders to psychotropic therapy.

154 Is Your Patient's Sex Life Dysfunctional? Check the Prolactin Level!

Abnormal libido and erectile dysfunction are well recognised after lung transplantation, however galactorrhea is reported rarely. We assessed the incidence and mechanisms involved in the development of hyperprolactinemia as a cause of these symptoms.

Role of noradrenaline in the development of dopamine-induced hyperprolactinemia

Hyperprolactinemia is neurodegenerative disease that develops in humans as a result of degeneration of dopaminergic (DA-ergic) neurons of the arcuate nucleus, which synthesize DA, a neurohormone inhibiting prolactin secretion by pituitary lactotropes. The design and detailed analysis of good experimental models of hyperprolactinemia may help us to understand the causes and mechanisms of the disease development and develop early diagnostics and treatment of the disease. Hyperprolactinemia is usually modeled in experiments using 6-hydroxydopamine (6-HDA), a neurotoxin causing degeneration of DA-ergic neurons of the arcuate nucleus. However, 6-HAD also induces degeneration of noradrenergic (NA-ergic) axons involved in the regulation of prolactin secretion. Therefore, in this study, we evaluated the role of NA in the development of hyperprolactinemia during degeneration of DA-ergic neurons of the arcuate nucleus. To this aim, we compared changes in DA and NA metabolism in the arcuate nucleus and the blood level of prolactin in rats after treatment with 6-HDA alone and 6-HDA in the presence of desmethylimipramine, drug that prevents degeneration of NA-ergic neurons. Studies were performed in 14 days after toxin administration, i.e., at a time point when toxin-induced degenerative processes are finished, and in 45 days, i.e., after initiation of compensatory processes. We found that, in 14 days after administration of pharmacological agents, hyperprolactinemia, which resulted from DA deficit due to degeneration of DA-ergic neurons of the arcuate nucleus, is enhanced when NA-ergic afferents are protected, which may be related to the inhibitory effect of NA on DA synthesis. The latter hypothesis is supported by the fact that in 45 days after treatment with 6-HDA alone, i.e., after combined degeneration of DA-ergic and NA-ergic neurons, DA synthesis in the arcuate nucleus returns back to the normal level, which is accompanied by recovery of the normal blood level of prolactin. In contrast, in 45 days after administration of 6-HDA and desmethylimipramine, NA synthesis increases to the normal level but DA synthesis in the arcuate nucleus remains at low level, which is accompanied by an increased blood level of prolactin. Thus, our data suggest that NA inhibits DA synthesis in the arcuate nucleus and prevents a compensatory increase in DA synthesis and the normalization of the blood level of prolactin during degeneration of DA-ergic neurons.

Adenohypophyseal Function in Dogs with Primary Hypothyroidism and Nonthyroidal Illness

A recent study of dogs with induced primary hypothyroidism (PH) demonstrated that thyroid hormone deficiency leads to loss of thyrotropin (TSH) hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with large vacuolated "thyroid deficiency" cells that double-stained for growth hormone (GH) and TSH, indicative of transdifferentiation of somatotropes to thyrosomatropes. Similar functional changes in adenohypophyseal function occur in dogs with spontaneous PH as do in dogs with induced PH, but not in dogs with nonthyroidal illness (NTI). Fourteen dogs with spontaneous PH and 13 dogs with NTI. Adenohypophyseal function was investigated by combined intravenous administration of 4 hypophysiotropic releasing hormones (4RH test), followed by measurement of plasma concentrations of ACTH, GH, luteinizing hormone (LH), prolactin (PRL), and TSH. In the PH dogs this test was repeated after 4 and 12 weeks of thyroxine treatment. In 6 PH dogs, the basal TSH concentration was within the reference range. In the PH dogs, the TSH concentrations did not increase with the 4RH test. However, TSH concentrations increased significantly in the NTI dogs. Basal and stimulated GH and PRL concentrations indicated reversible hypersomatotropism and hyperprolactinemia in the PH dogs, but not in the NTI dogs. Basal and stimulated LH and ACTH concentrations did not differ between groups. Dogs with spontaneous PH hypersecrete GH but have little or no TSH hypersecretion. Development of hyperprolactinemia (and possible galactorrhea) in dogs with PH seems to occur only in sexually intact bitches. In this group of dogs with NTI, basal and stimulated plasma adenohypophyseal hormone concentrations were not altered.

Compensatory reaction during degeneration of arcuate nucleus dopaminergic neurons in rats

The study has been carried out to verify the authors' hypothesis that degeneration of dopaminergic (DA-ergic) neurons of the hypothalamic tuberoinfundibular system and concomitant development of hyperprolactinemia are accompanied by involvement of compensatory synthesis of dopamine (DA) by non-dopaminergic neurons expressing single complementary enzymes of synthesis of this neurotransmitter. Degeneration of DA-ergic neurons was produced by a stereotaxic injection into the brain lateral ventricles of 6-hydroxydopamine (6-OHDA) - a specific neurotoxin of DA-ergic neurons. 14 and 45 days after the toxin administration there were determined concentration of prolactine in peripheral blood by methods of immunoenzyme and radioimmunological analyses as well as the DA amount in the arcuate nucleus by the method of highly efficient liquid chromatography with electrochemical detection. In a part of the animals, slices were prepared from the mediobasal hypothalamus (arcuate nucleus and medial eminence) and perfused with Krebs-Ringer medium; then the DA concentration was determined in the slices and in the incubation medium. 14 days after the neurotoxin administration there were revealed an increase of blood prolactine concentration and a decrease of DA concentration in the arcuate nucleus in vivo as well a decrease of the total DA amount in the slices and incubation medium in experiments in vitro. 45 days after the neurotoxin administration, all the above parameters returned to the normal level. This, the obtained data indicate that the hyperlactinemia and DA deficit appearing during degeneration of the arcuate nucleus DA-ergic neurons seem to be compensated due to an enhancement of DA synthesis by non-dopaminergic monoenzyme neurons of arctuate nucleus.

Ovarian dependence for pituitary tumorigenesis in D2 dopamine receptor-deficient mice.

Hypophyseotropic dopamine exerts a tonic inhibitory tone on pituitary lactotrophs by the activation of dopamine D2 receptors (D2R). Ablation of D2R through gene knock-out approaches results in hyperprolactinemia and prolactinomas. This phenotype is more severe and develops more rapidly in female mice. We tested whether the female hypersensitivity is due solely to the loss of D2R inhibitory tone or concomitant stimulation by ovarian factors. C57BL/6J congenic D2R(-/-) mice were ovariectomized at 2 months of age and serum PRL levels were measured serially. Ovariectomy attenuated hyperprolactinemia and after 18 months, D2R(-/-) mice had average pituitary weights of 4 mg, compared with 60 mg in the intact group. 17beta-Estradiol did not restore PRL secretion or pituitary weight. Although the pharmacologic dose of estradiol slightly increased pituitary weight in wild-type and D2R(-/-) mice, it inhibited serum PRL in both intact and ovariectomized females and in castrated males. For comparison, we tested the estradiol response of wild-type 129S6/SvEv mice in the same paradigm and found the expected increase in pituitary weight and serum PRL. Our results demonstrate that the development of hyperprolactinemia and prolactinomas in mice lacking D2R is dependent on ovarian stimulation and likely involves a factor(s) in addition to estrogen. Furthermore, we showed that estradiol-induced proliferation and PRL secretion can be differentially regulated in a strain-specific manner. These findings illustrate the importance of genetic background when analyzing endocrine regulation in mutant mouse models.

The Dominant Role of Increased Intrasellar Pressure in the Pathogenesis of Hypopituitarism, Hyperprolactinemia, and Headaches in Patients with Pituitary Adenomas*

Mild hyperprolactinemia frequently accompanies the hypopituitarism seen in patients with pituitary macroadenomas that do not secrete PRL. Recent data suggested that the hypopituitarism and mild hyperprolactinemia in this setting are largely due to compression of pituitary stalk and portal vessels. Headaches (HAs) are frequently seen in patients with large adenomas and at times in those with microadenomas. Because the walls of the sella turcica are relatively rigid, we postulate that tumor growth within the sella increases intrasellar pressure (ISP), which in turn impairs portal blood flow, resulting in mild hyperprolactinemia and hypopituitarism. We also postulate that increased mean ISP (MISP) contributes to the development of HAs. Normal MISP is not known but is unlikely to exceed normal intracranial pressure of less than 10-15 mm Hg. We determined MISP in 49 patients who had transsphenoidal surgery for pituitary adenomas. MISP was measured using a commonly available intracranial monitoring kit where a fiberoptic transducer was inserted through a 2-mm dural incision at the time of adenomectomy. Patients with deficient FSH, LH, ACTH, or TSH secretion were considered hypopituitary. Data on serum PRL levels were included for analysis only in patients whose adenomas had negative immunostaining for the hormone. MISP measurements ranged from 7-56 mm Hg, with a mean (+/-SD) of 28.8 +/- 13.5 and a median of 26 mm Hg. The pressure measurements were higher in patients with hypopituitarism than in those with normal pituitary function (P = 4.6013 x 10(-6)). Patients presenting with HAs had higher MISP than those who did not (P = 5.44 x 10(-7)), regardless of their pituitary function or tumor sizes. PRL levels correlated positively with MISP values (r = 0.715, P < 0.0001). Tumor size did not correlate with MISP or PRL levels. The findings of increased MISP in hypopituitary patients and the documented correlation with PRL levels, suggest that ISP is a major mechanism involved in the pathogenesis of hypopituitarism and hyperprolactinemia. Similarly, the increased MISP in patients with HAs, irrespective of tumor size or pituitary function, suggest that increased ISP is a major mechanism involved in the pathogenesis of this symptom. The data support the hypothesis that in patients with pituitary adenomas increased ISP is a major mechanism contributing to the development of hyperprolactinemia, hypopituitarism, and HAs. Increased ISP in these patients leads to compression of the portal vessels and the associated interruption of the delivery of hypothalamic hormones to the anterior pituitary. This would explain the reversibility of pituitary function observed in most patients after adenomectomy. However, increased ISP may also lead to decreased blood supply, resulting in ischemic necrosis in some regions of the pituitary. The latter could limit potential recovery of pituitary function after adenomectomy.

Pattern of Development of Hyperprolactinemia After Initiation of Haloperidol Therapy

Pattern of Development of Hyperprolactinemia After Initiation of Haloperidol Therapy

Elevated serum prolactin level with high-dose estrogen contraceptive pills

Background and objectives There are currently groups of women using high-dose estrogen contraceptive pills, especially in the developing countries. The aim of this study was to determine the correlation between the duration of contraceptive pill intake, the dose of steroid contained in the contraceptive pills and the incidence and degree of serum prolactin level elevation in those women.Study design This study was conducted in 100 contraceptive pill users. Women were randomly selected for this study with an age range from 19 to 35 years and duration of contraceptive pill intake from 6 to 120 months. Cases were classified into two groups. The first group (50 cases) were taking high-dose estrogen pills (50 μg) and the second group (50 cases) were taking low-dose estrogen pills (30 μg).Results The results of the present study showed that there was a significant elevation in serum prolactin level in both groups, with a more significant elevation in the high-dose pill users.Conclusions There is a positive relationship between serum prolactin level and the duration of pill intake and their steroid content, and this relationship is not related to the age and parity of the women. The groups of women studied are scheduled for follow-up to determine if there is any future drawback which results as a consequence of the developed hyperprolactinemia. Prolactin determination should be considered for all women prior to pill intake. This determination of serum prolactin level prior to pill use will be useful in the evaluation of the future relationship between the estrogen content of the pills and the later development of hyperprolactinemia.

Prolactin response to anesthetic stress and beta-endorphin is altered in female rats treated neonatally with monosodium glutamate

MSG (4 mg/g, sc) or saline was administered to neonatal female rats on day 1, 3, 5, 7 and 9. Study 1) Prl levels were assessed at 30, 60 and 75 days after birth to monitor possible development of hyperprolactinemia. No hyperprolactinemia was observed at any time studied. Study 2) MSG and control rats were administered pentobarbital anesthesia at 2 months of age. At 20, 60 and 90 min following anesthesia, plasma was collected for assay of Prl. 20 min prior to the 90 min bleeding, BE ( 5 μg 5 ul ) was stereotaxically administered, into the third ventricle. MSG-treated rats had an attenuated Prl response to the stress of anesthesia (bleeding 1). Prl levels in control and MSG-treated rats were similar at 60 min post-anesthesia (bleeding 2) which represented a return of Prl levels to baseline after stress-induced elevation of Prl. Control and MSG-treated rats exhibited an increase in plasma Prl following intracerebroventricular BE; however, the amplitude of this response was markedly attenuated in the MSG-treated animals (bleeding 3). Thus, an observed loss of TH-positive neurons in the arcuate nucleus of the hypothalamus following MSG treatment and the attenuated response of Prl to anesthesia-stress and BE administration suggests that Prl secretion in response to these agents is operative through inhibition of the TIDA system. Furthermore, these studies show that the Prl response to these agents (anesthetic and BE) is intact but sub-operational in MSG-treated rats.

Age-related changes in prolactin secretion and the population of mammotrophs in the rat: A longitudinal study

The concentration of prolactin (PRL) in the blood increases with aging in the rat, and pituitary prolactinomas often develop in aged female rats. We measured blood PRL levels in the course of development of hyperprolactinemia and prolactinomas in individual rats by serial sampling of the blood of living rats. The pituitaries were examined upon the death of the rats to detect prolactinomas by immunocytochemical staining. Hyperprolactinemia in rats without pituitary tumors was inevitably followed by the development of a prolactinoma within 3 months. Rats which had no tumors at the time of death had low PRL levels throughout their lifespan. Counting of anterior pituitary cells after immunocytochemical staining for electron microscopy indicated that the number of mammotrophs increased and that the number of somatotrophs decreased in rats with hyperprolactinemia. Based on these results, we conclude that age-related hyperprolactinemia in female rats represents a precancerous state for prolactinoma.

Changes in the Kinetics of [3H]Dopamine Release from Median Eminence and Striatal Synaptosomes during Aging*

The release of preaccumulated tritium-labeled dopamine [( 3H]DA) was examined in isolated nerve terminals (synaptosomes) prepared from the median eminence (ME) and corpus striatum (CS) of young (2-3 months), middle-aged (11-12 months), and old (19-21 months) male rats. Fractional release of [3H]DA was measured over 1- to 10-sec time intervals under basal (5 mM K+) and depolarizing (75 mM K+) conditions in the presence of calcium. No differences in the rate of basal efflux between the age groups were observed in either ME or CS preparations. Fast-phase evoked [3H]DA release (0-1 sec) from CS synaptosomes was unchanged from young to middle-aged, but was decreased in old preparations. These data demonstrate that the nigrostriatal nerve terminal has a diminished ability to respond fully to depolarizing stimuli in advanced age. Mean serum PRL levels in old rats were 2.3-fold greater than those in both young and middle-aged rats, while serum LH levels were decreased 2.0-fold in middle-aged and old compared with those in young rats. The fact that LH levels were already decreased in middle-aged rats while PRL levels had not yet increased suggests that decreased gonadotropin titers in old rats do not result from the coincident hyperprolactinemia. In ME synaptosomes, depolarization-induced [3H]DA release was decreased at all time points in middle-aged preparations compared to that in young preparations. The reduced fractional release from the middle-aged ME synaptosomes was due to a depressed rate of release during the initial second of depolarization. Evoked release from ME terminals of old rats was comparable to that measured in the young group. Thus, there occurred an age-related biphasic change in the initial rate of evoked DA release from ME synaptosomes. Diminished response of ME dopaminergic terminals to depolarizing stimuli during middle age may be important in the later development of hyperprolactinemia in aging male rats. The increased PRL available for feedback on the tuberoinfundlbular dopaminergic neurons may, in turn, be associated with the apparent recovery of evoked [3H]DA release from ME synaptosomes of old rats.

Unremitting suppression of the postovariectomy rise in plasma LH by tumor-induced hyperprolactinemia.

The plasma LH response to ovariectomy was studied at different periods in the development of hyperprolactinemia in rats bearing the transplantable prolactin-secreting pituitary tumors 7315a or MtTW15. Rats were subcutaneously inoculated with tumor cells and ovariectomy was performed at 3 times during the subsequent growth of the solid tumor: (1) coincident with tumor cell implantation; (2) when solid tumors first became palpable, and (3) when solid tumors were large. The values for circulating prolactin and LH were serially determined following ovariectomy for 63, 35 and 28 days, respectively. In other studies, tumor cells were implanted into animals which had undergone ovariectomy 3 months earlier. In the presence of hyperprolactinemia caused by the prolactin secreting tumors, the plasma LH following ovariectomy was either reduced following an initial increase, prevented from increasing, or reduced from chronically elevated levels. Hyperprolactinemia of approximately 7-50 micrograms/ml caused marked suppression of LH secretion, while hyperprolactinemia in the range of 0.2-6 micrograms/ml resulted in significant but slower and lesser suppression of LH which did not reach noncastrate levels. The inhibitory effect of hyperprolactinemia on plasma LH after ovariectomy was persistent and unremitting for the duration of each experiment, and there was no tendency for suppressed LH to return to levels expected for the ovariectomized state. The model of hyperprolactinemia induced with transplantable prolactin-secreting tumors in the ovariectomized rat may prove to be valuable in understanding the mechanism of depression of gonadal function by hyperprolactinemia.

Hyperprolactinemia and galactorrhea: spontaneous versus iatrogenic hypothyroidism.

Although hyperprolactinemia and galactorrhea occur in primary hypothyroidism, factors influencing their presence are not well established. To further define these factors, the duration of illness and serum levels of PRL and TSH were investigated in a group of 50 patients with spontaneous (27 females and 7 males) and iatrogenic (16 females) primary hypothyroidism. To test the hypothesis of reduced hypothalamic dopamine content in over long-standing primary hypothyroidism, the percent increase in serum PRL after the administration of metoclopramide, a dopamine blocker (2.5 mg, iv bolus), was studied in 13 women with spontaneous primary hypothyroidism and compared with that in 10 euthyroid women. While 88.2% of the patients with spontaneous primary hypothyroidism were hyperprolactinemia, only 31% of those with iatrogenic disease had elevated PRL levels. Women with spontaneous primary hypothyroidism had a longer duration of illness (72 +/- 12 vs. 6.7 +/- 1.8 months; P less than 0.001) and higher serum TSH (189 +/- 32 vs. 68 +/- 14 microunits/ml; P less than 0.01) and PRL levels (49.8 +/- 5.6 vs. 20.9 +/- 0.8 ng/ml; P less than 0.001) than women with iatrogenic hypothyroidism. A linear correlation existed between PRL and duration of illness (r = 0.53; P less than 0.001), while a logarithmic correlation was found between PRL and TSH levels (r = 0.44; P less than 0.01). Even though the duration of illness and TSH levels were similar in women with spontaneous disease with (n = 7) or without (n = 20) galactorrhea, the former were significantly younger (39.3 +/- 1.8 vs. 56.6 +/- 3 yr; P less than 0.001), and their PRL levels were significantly higher (69.3 +2- 8.9 vs. 42.9 +/- 2.2 ng/ml; P less than 0.001). The PRL response to metoclopramide in women with spontaneous disease was significantly smaller than that in controls (194 +/- 39% vs. 446 +/- 40%; P less than 0.001) and inversely correlated with basal PRL levels (r = -0.55; P less than 0.05). These data indicate that in primary hypothyroidism 1) the duration of illness is important in the development of hyperprolactinemia, 2) galactorrhea is more common in young women with spontaneous disease and high PRL levels, and 3) hypothalamic dopamine appears reduced in spontaneous disease.